This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. RNA-dependent RNA polymerases are commonly found in pathogenic viruses from Hepatitis C (HCV) to the common cold (rhinovirus). Structures of RNA-dependent RNA polymerases show a remarkable amount of conservation exhibiting an overall fold with three major domains (palm, fingers and thumb) arranged like a right hand. This strong structural conservation makes viral RNA-dependent RNA polymerases a compelling target for antiviral compounds. Our research focuses on understanding how RNA-dependent RNA polymerases function in order to rationally develop broad acting antiviral compounds.